Age-related macular degeneration (AMD) is a scourge of the elderly, with some stage of this potentially blinding disease present in approximately a third of individuals over 75 years of age in the US. There is substantial evidence that AMD is an inflammatory disease involving dysregulation of the complement pathway. We found that the hapten, CEP (carboxyethylpyrrole), generated by oxidative damage to docosahexaenoic acid (DHA), is present as an adduct on drusen proteins in AMD donor eyes. In addition, autoantibodies against CEP were more abundant in the circulation (plasma) of individuals with AMD than in age-matched individuals without AMD. Because DHA is abundant in the outer retina where light and high oxygen levels provide a permissive environment for oxidative damage, this tissue is a likely source of CEP-adducts. Since CEP-adducts is antigenic, we speculated that as the outer retina generates these adducts, the immune system becomes responsive to these new epitopes and over time begins to attack the cells that are the source of this fragment. To test this hypothesis we immunized normal mice with CEP-adducted mouse serum albumin (CEP-MSA). Our prediction was that systemic immunization with CEP would sensitize mice to endogenous CEP-adducts generated in the outer retina during the normal course of aging. In turn the immune system would respond by attacking the cells where CEP epitopes are most readily generated. We found that immunized mice develop antibodies to CEP, fix complement component-3 in Bruch's membrane, accumulate drusen below the RPE during aging, and develop lesions in the RPE mimicking geographic atrophy, the end-stage condition characteristic of dry AMD. The research proposed here uses this mouse model for mechanistic studies on the role of complement activation pathways in producing the pathology, the role of antibody in causing the lesions observed, and the possibility of prevention of the lesions through manipulation of complement activation or suppression of the pathology with oral tolerance. Outcomes from these studies have the potential to lead to the identification of new therapeutic pathways to prevent AMD. PUBLIC HEALTH RELEVANCE: The loss of central vision from age-related macular degeneration is the bane of the elderly in industrialized nations. Until recently so little was known about the mechanism of this disease that there was no potential for developing animal models for this disorder. This has now changed with the findings that oxidative damage to retinal lipids is a source of an inflammatory signal that may target this tissue for immune system mediated pathology. This inflammatory signal has been identified, synthesized and used to produce AMD-like lesions in mice. Studies proposed in this grant use this mouse model to understand several aspects of the disease process and explore possible routes of therapeutic intervention.